Michael B Liu1,2, Silvia G Priori3,4,5, Zhilin Qu1,6, James N Weiss1,2. 1. Departments of Medicine/Cardiology (M.B.L., Z.Q., J.N.W.), David Geffen School of Medicine, University of California, Los Angeles. 2. Physiology (M.B.L., J.N.W.), David Geffen School of Medicine, University of California, Los Angeles. 3. Department of Molecular Medicine, University of Pavia, Italy (S.G.P.). 4. Istituti Clinici Scientifici Maugeri, IRCCS, Pavia Italy (S.G.P.). 5. Centro de Investigaciones Cardiovasculares Carlos III, Madrid, Spain (S.G.P.). 6. Computational Medicine (Z.Q.), David Geffen School of Medicine, University of California, Los Angeles.
Abstract
BACKGROUND: In cardiac gene therapy to improve contractile function, achieving gene expression in the majority of cardiac myocytes is essential. In preventing cardiac arrhythmias, however, this goal may not be as important since transduction efficiencies as low as 40% suppressed ventricular arrhythmias in genetically modified mice with catecholaminergic polymorphic ventricular tachycardia. METHODS: Using computational modeling, we simulated 1-, 2-, and 3-dimensional tissue under a variety of conditions to test the ability of genetically engineered nonarrhythmogenic stabilizer cells to suppress triggered activity due to delayed or early afterdepolarizations. RESULTS: Due to source-sink relationships in cardiac tissue, a minority (20%-50%) of randomly distributed stabilizer cells engineered to be nonarrhythmogenic can suppress the ability of arrhythmogenic cells to generate delayed and early afterdepolarizations-related arrhythmias. Stabilizer cell gene therapy strategy can be designed to correct a specific arrhythmogenic mutation, as in the catecholaminergic polymorphic ventricular tachycardia mice studies, or more generally to suppress delayed or early afterdepolarizations from any cause by overexpressing the inward rectifier K channel Kir2.1 in stabilizer cells. CONCLUSIONS: This promising antiarrhythmic strategy warrants further testing in experimental models to evaluate its clinical potential.
BACKGROUND: In cardiac gene therapy to improve contractile function, achieving gene expression in the majority of cardiac myocytes is essential. In preventing cardiac arrhythmias, however, this goal may not be as important since transduction efficiencies as low as 40% suppressed ventricular arrhythmias in genetically modified mice with catecholaminergic polymorphic ventricular tachycardia. METHODS: Using computational modeling, we simulated 1-, 2-, and 3-dimensional tissue under a variety of conditions to test the ability of genetically engineered nonarrhythmogenic stabilizer cells to suppress triggered activity due to delayed or early afterdepolarizations. RESULTS: Due to source-sink relationships in cardiac tissue, a minority (20%-50%) of randomly distributed stabilizer cells engineered to be nonarrhythmogenic can suppress the ability of arrhythmogenic cells to generate delayed and early afterdepolarizations-related arrhythmias. Stabilizer cell gene therapy strategy can be designed to correct a specific arrhythmogenic mutation, as in the catecholaminergic polymorphic ventricular tachycardiamice studies, or more generally to suppress delayed or early afterdepolarizations from any cause by overexpressing the inward rectifier K channel Kir2.1 in stabilizer cells. CONCLUSIONS: This promising antiarrhythmic strategy warrants further testing in experimental models to evaluate its clinical potential.
Authors: J Andrew Wasserstrom; Yohannes Shiferaw; Wei Chen; Satvik Ramakrishna; Heetabh Patel; James E Kelly; Matthew J O'Toole; Amanda Pappas; Nimi Chirayil; Nikhil Bassi; Lisa Akintilo; Megan Wu; Rishi Arora; Gary L Aistrup Journal: Circ Res Date: 2010-09-09 Impact factor: 17.367
Authors: Makarand Deo; Yanfei Ruan; Sandeep V Pandit; Kushal Shah; Omer Berenfeld; Andrew Blaufox; Marina Cerrone; Sami F Noujaim; Marco Denegri; José Jalife; Silvia G Priori Journal: Proc Natl Acad Sci U S A Date: 2013-02-25 Impact factor: 11.205